tbuckley/cabot-search huggingface dataset:
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response
Authors: Shawn H. R. Lee, Wenjian Yang, Yoshihiro Gocho, August John, Lauren Rowland, Brandon Smart, Hannah Williams, Dylan Maxwell, Jeremy Hunt, Wentao Yang, Kristine R. Crews, Kathryn G. Roberts, Sima Jeha, Cheng Cheng, Seth E. Karol, Mary V. Relling, Gary L. Rosner, Hiroto Inaba, Charles G. Mullighan, Ching-Hon Pui, William E. Evans, Jun J. Yang
Journal: Nature Medicine (2023)

Abstract Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer.
Matching researchers’ needs and patients’ contributions: practical tips for meaningful patient engagement from the field of rheumatology
Authors: Casper G Schoemaker, Dawn P Richards, Maarten de Wit
Journal: Annals of the Rheumatic Diseases (2023)

There is an increasing recognition of the importance of patient engagement and involvement in health research, specifically within the field of rheumatology. In general, researchers in this specialty appreciate the value of patients as partners in research. In practice, however, the majority of researchers does not involve patients on their research teams. Many researchers find it difficult to match their needs for patient engagement and the potential contributions from individuals living with rheumatic disease. In this Viewpoint, we provide researchers and patients practical tips for matching ‘supply and demand,’ based on our own experiences as patient engagement consultants and trainers in rheumatology research. All authors started as a ‘naïve’ patient or caregiver, an identity that evolved through a process of ‘adversarial growth’: positive changes that are experienced as a result of the struggle with highly challenging life circumstances. Here, we introduce four stages of adversarial growth in the context of research. We submit that all types of patients have their own experiences, qualities and skills, and can add specific input to research. The recommendations for engagement are not strict directives. They are meant as starting points for discussion or interview. Regardless of individual qualities and knowledge, we believe that all patients engaged in research have a single goal in common: to contribute to research that ultimately will change the lives of many other patients.
Physiological functions of podosomes: From structure and function to therapy implications in osteoclast biology of bone resorption
Authors: Zhong-Hua Chen, Jun-Jie Wu, Dan-Yang Guo, Yue-Yue Li, Meng-Nan Chen, Zhen-Yu Zhang, Zheng-Dong Yuan, Kai-Wen Zhang, Wei-Wei Chen, Fan Tian, Jun-Xing Ye, Xia Li, Feng-Lai Yuan
Journal: Ageing Research Reviews (2023)
Gut commensal<i>Parabacteroides distasonis</i>alleviates inflammatory arthritis
Authors: Haijian Sun, Yunke Guo, Haidan Wang, Ailing Yin, Jing Hu, Tianjie Yuan, Shuxin Zhou, Weichen Xu, Peng Wei, Shusheng Yin, Panru Liu, Xi Guo, Yizhao Tang, Yujiao Yan, Zichen Luo, Majie Wang, Qingqing Liang, Peng Wu, Aifeng Zhang, Zhuxiu Zhou, Yueyue Chen, Yongming Li, Jing Li, Jinjun Shan, Wei Zhou
Journal: Gut (2023)

Gut microbiota dysbiosis is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify potential probiotic gut microbes that can ameliorate the development of RA.Microbiota profiling in patients with RA and healthy individuals was investigated via 16S rDNA bacterial gene sequencing and shotgun metagenomics. Collagen-induced arthritic mice and TNF-α transgenic mice were used to evaluate the roles of the gut commensal Parabacteroides distasonis in RA. The effects of P. distasonis-derived microbial metabolites on the differentiation of CD4+ T cells and macrophage polarisation were also investigated.The relative abundance of P. distasonis in new-onset patients with RA and patients with RA with history of the disease was downregulated and this decrease was negatively correlated with Disease Activity Score-28 (DAS28). Oral treatment of arthritic mice with live P. distasonis (LPD) considerably ameliorated RA pathogenesis. LPD-derived lithocholic acid (LCA), deoxycholic acid (DCA), isolithocholic acid (isoLCA) and 3-oxolithocholic acid (3-oxoLCA) had similar and synergistic effects on the treatment of RA. In addition to directly inhibiting the differentiation of Th17 cells, 3-oxoLCA and isoLCA were identified as TGR5 agonists that promoted the M2 polarisation of macrophages. A specific synthetic inhibitor of bile salt hydrolase attenuated the antiarthritic effects of LPD by reducing the production of these four bile acids. The natural product ginsenoside Rg2 exhibited its anti-RA effects by promoting the growth of P. distasonis.P. distasonis and ginsenoside Rg2 might represent probiotic and prebiotic agents in the treatment of RA.
Legacy of covid-19 for indigenous health in the Brazilian Amazon
Authors: Christine Ro
Journal: BMJ (2023)

Legacy of covid-19 for indigenous health in the Brazilian AmazonPre-existing vulnerabilities meant that covid-19 hit indigenous people particularly hard, but as Christine Ro reports, it also kickstarted initiatives to improve health Christine Ro freelance journalist "I don't want privileges.I just want the healthcare system to understand," says Marinete Tukano, treasurer coordinator of Makira E'ta, a network of indigenous women in the Brazilian state of Amazonas.
Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy
Authors: Jonathan W. Friedberg
Journal: Journal of Clinical Oncology (2023)

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES JCO Flashback: Evaluating Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed B-cell Lymphoma (1998). January 05, 2023 Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program. January 05, 2023 ARTICLE CITATION DOI: 10.1200/JCO.22.02425 Journal of Clinical Oncology - published online before print January 5, 2023 PMID: 36603540 Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy Jonathan W. Friedberg, MD, MMSc1,2,3xJonathan W. FriedbergSearch for articles by this author Show More 1Wilmot Cancer Institute, Rochester, NY2University of Rochester, Rochester, NY3Editor-in-Chief, Journal of Clinical Oncology, Alexandria, VA https://doi.org/10.1200/JCO.22.02425 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn 1998, McLaughlin et al1 demonstrated that nearly half of patients with relapsed and refractory indolent B-cell lymphoma responded to single-agent anti-CD20 monoclonal antibody treatment with rituximab, with a median progression-free survival exceeding 12 months. The impact of this trial on patients with B-cell lymphomas cannot be overstated, as it directly led to the first US Food and Drug administration (FDA) approval of an oncologic monoclonal antibody and the development of subsequent studies resulting in major improvements in outcomes across a broad spectrum of B-cell–mediated diseases.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTFlashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody TherapyThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Jonathan W. FriedbergThis author is the Editor-in-Chief of Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Research Funding: Enterome (Inst)Patents, Royalties, Other Intellectual Property: Patient on bone marrow microenvironment signalsNo other potential conflicts of interest were reported. Companion JCO Flashback: Evaluating Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed B-cell Lymphoma (1998) Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program
Faecal microbiota transplantation for first and second episodes of Clostridioides difficile infection – Authors' reply
Authors: Simon Mark Dahl Baunwall, Sara Ellegaard Andreasen, Mette Mejlby Hansen, Jens Kelsen, Katrine Lundby Høyer, Nina Rågård, Lotte Lindgreen Eriksen, Sidsel Støy, Tone Rubak, Else Marie Skjøde Damsgaard, Susan Mikkelsen, Christian Erikstrup, Jens Frederik Dahlerup, Christian Lodberg Hvas
Journal: The Lancet. Gastroenterology & hepatology (2023)
The gut microbiota in multiple sclerosis varies with disease activity
Authors: Florence Thirion, Finn Sellebjerg, Yong Fan, Liwei Lyu, Tue H. Hansen, Nicolas Pons, Florence Levenez, Benoit Quinquis, Evelina Stankevic, Helle B. Søndergaard, Thomas M. Dantoft, Casper S. Poulsen, Sofia K. Forslund, Henrik Vestergaard, Torben Hansen, Susanne Brix, Annette Oturai, Per Soelberg Sørensen, Stanislav D. Ehrlich, Oluf Pedersen
Journal: Genome Medicine (2023)

Abstract Background Multiple sclerosis is a chronic immune-mediated disease of the brain and spinal cord resulting in physical and cognitive impairment in young adults. It is hypothesized that a disrupted bacterial and viral gut microbiota is a part of the pathogenesis mediating disease impact through an altered gut microbiota-brain axis. The aim of this study is to explore the characteristics of gut microbiota in multiple sclerosis and to associate it with disease variables, as the etiology of the disease remains only partially known. Methods Here, in a case-control setting involving 148 Danish cases with multiple sclerosis and 148 matched healthy control subjects, we performed shotgun sequencing of fecal microbial DNA and associated bacterial and viral microbiota findings with plasma cytokines, blood cell gene expression profiles, and disease activity. Results We found 61 bacterial species that were differentially abundant when comparing all multiple sclerosis cases with healthy controls, among which 31 species were enriched in cases. A cluster of inflammation markers composed of blood leukocytes, CRP, and blood cell gene expression of IL17A and IL6 was positively associated with a cluster of multiple sclerosis-related species. Bacterial species that were more abundant in cases with disease-active treatment-naïve multiple sclerosis were positively linked to a group of plasma cytokines including IL-22, IL-17A, IFN-β, IL-33, and TNF-α. The bacterial species richness of treatment-naïve multiple sclerosis cases was associated with number of relapses over a follow-up period of 2 years. However, in non-disease-active cases, we identified two bacterial species, Faecalibacterium prausnitzii and Gordonibacter urolithinfaciens , whose absolute abundance was enriched. These bacteria are known to produce anti-inflammatory metabolites including butyrate and urolithin. In addition, cases with multiple sclerosis had a higher viral species diversity and a higher abundance of Caudovirales bacteriophages . Conclusions Considerable aberrations are present in the gut microbiota of patients with multiple sclerosis that are directly associated with blood biomarkers of inflammation, and in treatment-naïve cases bacterial richness is positively associated with disease activity. Yet, the finding of two symbiotic bacterial species in non-disease-active cases that produce favorable immune-modulating compounds provides a rationale for testing these bacteria as adjunct therapeutics in future clinical trials.
Molecular profiling of EBV associated diffuse large B-cell lymphoma
Authors: Fabian Frontzek, Annette M. Staiger, Ramona Wullenkord, Michael Grau, Myroslav Zapukhlyak, Katrin S. Kurz, Heike Horn, Tabea Erdmann, Falko Fend, Julia Richter, Wolfram Klapper, Peter Lenz, Stephan Hailfinger, Anna Tasidou, Marcel Trautmann, Wolfgang Hartmann, Andreas Rosenwald, Leticia Quintanilla-Martinez, German Ott, Ioannis Anagnostopoulos, Georg Lenz
Journal: Leukemia (2023)

Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical outcome. EBV infection of lymphoma cells has been associated with different lymphoma subtypes while the precise role of EBV in lymphomagenesis and specific molecular characteristics of these lymphomas remain elusive. To further unravel the biology of EBV associated DLBCL, we present a comprehensive molecular analysis of overall 60 primary EBV positive (EBV+) DLBCLs using targeted sequencing of cancer candidate genes (CCGs) and genome-wide determination of recurrent somatic copy number alterations (SCNAs) in 46 cases, respectively. Applying the LymphGen classifier 2.0, we found that less than 20% of primary EBV + DLBCLs correspond to one of the established molecular DLBCL subtypes underscoring the unique biology of this entity. We have identified recurrent mutations activating the oncogenic JAK-STAT and NOTCH pathways as well as frequent amplifications of 9p24.1 contributing to immune escape by PD-L1 overexpression. Our findings enable further functional preclinical and clinical studies exploring the therapeutic potential of targeting these aberrations in patients with EBV + DLBCL to improve outcome.
Increase in invasive group A streptococcal (Streptococcus pyogenes) infections (iGAS) in young children in the Netherlands, 2022
Authors: Brechje de Gier, Niek Marchal, Ilse de Beer-Schuurman, Margreet te Wierik, Mariëtte Hooiveld, Hester E. de Melker, Nina M. van Sorge
Journal: Eurosurveillance (2023)

In 2022, a sevenfold increase in the number of notifiable invasive
Increase in invasive group A streptococcal infection notifications, England, 2022
Authors: Rebecca Guy, Katherine L Henderson, Juliana Coelho, Helen Hughes, Emily L Mason, Sarah M Gerver, Alicia Demirjian, Conall Watson, Ashley Sharp, Colin S Brown, Theresa Lamagni
Journal: Eurosurveillance (2023)

Increases in invasive group A streptococcal (iGAS) infection and associated deaths, particularly in children, above seasonally expected levels are being seen this season (772 notifications reported in weeks 37 to 48 in 2022) across England. Diagnoses of iGAS infection from lower respiratory tract specimens in children under 15 years increased to 28% in November 2022. Medical practitioners have been alerted to the exceptional increase in incidence, including unusual numbers of children presenting with pulmonary empyema.
Early and intense epidemic of respiratory syncytial virus (RSV) in Denmark, August to December 2022
Authors: Charlotte Munkstrup, Frederikke Kristensen Lomholt, Hanne-Dorthe Emborg, Karina Lauenborg Møller, Jesper Schak Krog, Ramona Trebbien, Lasse S. Vestergaard
Journal: Eurosurveillance (2023)

In the autumn of 2022, Denmark witnessed the second out-of-season epidemic of respiratory syncytial virus (RSV) following widespread societal preventive measures implemented against the coronavirus disease (COVID-19) pandemic during 2020 and 2021. Admissions peaked at twice the level of pre-pandemic seasons. Especially infants below 6 months of age were affected, but also adults over 45 years of age. The current epidemic is dominated by RSV subtype B, unlike the major RSV summer epidemic in 2021 dominated by RSV subtype A.
Molecular surveillance of multidrug-resistant Gram-negative bacteria in Ukrainian patients, Germany, March to June 2022
Authors: Tilman Schultze, Michael Hogardt, Erwin Sanabria Velázquez, Daniel Hack, Silke Besier, Thomas A Wichelhaus, Ulrich Rochwalsky, Volkhard AJ Kempf, Claudia Reinheimer
Journal: Eurosurveillance (2023)

BackgroundSince the beginning of the war in Ukraine in February 2022, Ukrainians have been seeking shelter in other European countries.AimWe aimed to investigate the prevalence and the molecular epidemiology of multidrug-resistant Gram-negative (MDRGN) bacteria and meticillin-resistant Staphylococcus aureus (MRSA) in Ukrainian patients at admittance to the University Hospital Frankfurt, Germany.MethodsWe performed screening and observational analysis of all patients from March until June 2022. Genomes of MDRGN isolates were analysed for antimicrobial resistance, virulence genes and phylogenetic relatedness.ResultsWe included 103 patients (median age: 39 ± 23.7 years), 57 of whom were female (55.3%; 95% confidence interval (CI): 45.2-5.1). Patients were most frequently admitted to the Department of Paediatrics (29/103; 28.2%; 95% CI: 19.7-37.9). We found 34 MDRGN isolates in 17 of 103 patients (16.5%; 95% CI: 9.9-25.1). Ten patients carried 21 carbapenem-resistant (CR) bacteria, five of them more than one CR isolate. Four of six patients with war-related injuries carried eight CR isolates. In six of 10 patients, CR isolates caused infections. Genomic characterisation revealed that the CR isolates harboured at least one carbapenemase gene, blaNDM-1 being the most frequent (n = 10). Core genome and plasmid analysis revealed no epidemiological connection between most of these isolates. Hypervirulence marker genes were found in five of six Klebsiella pneumoniae CR isolates. No MRSA was found.ConclusionHospitals should consider infection control strategies to cover the elevated prevalence of MDRGN bacteria in Ukrainian patients with war-related injuries and/or hospital pre-treatment and to prevent the spread of hypervirulent CR isolates.
Detecting early signals of COVID-19 outbreaks in 2020 in small areas by monitoring healthcare utilisation databases: first lessons learned from the Italian Alert_CoV project
Authors: Ivan Merlo, Mariano Crea, Paolo Berta, Francesca Ieva, Flavia Carle, Federico Rea, Gloria Porcu, Laura Savaré, Raul De Maio, Marco Villa, Danilo Cereda, Olivia Leoni, Francesco Bortolan, Giuseppe Maria Sechi, Antonino Bella, Patrizio Pezzotti, Silvio Brusaferro, Gian Carlo Blangiardo, Massimo Fedeli, Giovanni Corrao
Journal: Eurosurveillance (2023)

BackgroundDuring the COVID-19 pandemic, large-scale diagnostic testing and contact tracing have proven insufficient to promptly monitor the spread of infections.AimTo develop and retrospectively evaluate a system identifying aberrations in the use of selected healthcare services to timely detect COVID-19 outbreaks in small areas.MethodsData were retrieved from the healthcare utilisation (HCU) databases of the Lombardy Region, Italy. We identified eight services suggesting a respiratory infection (syndromic proxies). Count time series reporting the weekly occurrence of each proxy from 2015 to 2020 were generated considering small administrative areas (i.e. census units of Cremona and Mantua provinces). The ability to uncover aberrations during 2020 was tested for two algorithms: the improved Farrington algorithm and the generalised likelihood ratio-based procedure for negative binomial counts. To evaluate these algorithms' performance in detecting outbreaks earlier than the standard surveillance, confirmed outbreaks, defined according to the weekly number of confirmed COVID-19 cases, were used as reference. Performances were assessed separately for the first and second semester of the year. Proxies positively impacting performance were identified.ResultsWe estimated that 70% of outbreaks could be detected early using the proposed approach, with a corresponding false positive rate of ca 20%. Performance did not substantially differ either between algorithms or semesters. The best proxies included emergency calls for respiratory or infectious disease causes and emergency room visits.ConclusionImplementing HCU-based monitoring systems in small areas deserves further investigations as it could facilitate the containment of COVID-19 and other unknown infectious diseases in the future.
Action value calculations in social context from infancy
Authors: Mitsuhiko Ishikawa, Atsushi Senju
Journal: Trends in Cognitive Sciences (2023)

Infants adaptively modulate their social behaviours, such as gaze-following, to social context. We propose that such modulations are based on infants' social decision-making, to achieve the most valuable outcome. We propose an 'action value calculator model', which formulates the cognitive mechanisms underlying, and the development of, the decision-making process during interactions.
Radiopharmaceuticals heat anti-tumor immunity
Authors: Qi Sun, Jiyuan Li, Zexuan Ding, Zhibo Liu
Journal: Theranostics (2023)

Radiopharmaceutical therapy (RPT) has proven to be an effective cancer treatment with minimal toxicity. With several RPT agents approved by FDA, the remarkable potential of this therapy is now being recognized, and the anti-tumor immunity induced by RPT is beginning to be noticed. This review evaluates the potential of RPT for immune activation, including promoting the release of danger associated-molecular pattern molecules that recruit inflammatory cells into the tumor microenvironment, and activating antigen-presenting cells and cytotoxic T cells. We also discuss the progress of combining RPT with immunotherapy to increase efficacy.
Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation
Authors: Yingying Lu, Zhijia Li, Shuangqian Zhang, Tongtong Zhang, Yanjun Liu, Lan Zhang
Journal: Theranostics (2023)

Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining mitochondria and intracellular homeostasis.In recent years, mitophagy has received increasing attention as a research hotspot related to the pathogenesis of clinical diseases, such as neurodegenerative diseases, cardiovascular diseases, cancer, metabolic diseases, and so on.It has been found that the regulation of mitophagy may become a new direction for the treatment of some diseases.In addition, numerous small molecule modulators of mitophagy have also been reported, which provides new opportunities to comprehend the procedure and potential of therapeutic development.Taken together, in this review, we summarize current understanding of the mechanism of mitophagy, discuss the roles of mitophagy and its relationship with diseases, introduce the existing small-molecule pharmacological modulators of mitophagy and further highlight the significance of their development.